The mTOR/AMPK signalling is considered master regulator of cell growth and energy homeostasis. Glutamine was reported to facilitate this, via α-ketoglutarate (αKG), which is associated with aggressive cancer. CaMKK2 (Calcium-Calmodulin Dependent Protein Kinase Kinase-2) is a well-characterised activator of AMPK with key roles in cellular metabolism and proliferation. TCGA and GTEx data mining indicates CaMKK2 overexpression to be at its highest level in prostate adenocarcinomas compared to normal counterparts and have inverse correlation with survival rate. While the knowledge generated so far accentuate the clinical importance of CaMKK2, its mechanisms of function in nutrient-deprived microenvironment remain poorly characterized. Being a kinase with restricted expression profile identifies CaMKK2 as a highly attractive therapeutic target. In fission yeast (S. pombe), Ssp1 and Ssp2 represent CaMKK2 and AMPK, respectively. Here we report a novel regulatory phosphorylation site on Ssp1 which is elevated under nutrient stress. In addition, yeast undergoing a nutrient stress showed an increase in αKG levels, and a mutation in this site results in decreased Ssp2 activation. Mutation of this site blocked αKG-mediated activation of CaMKK2 in human cells. Furthermore, we mapped the αKG binding pocket on CaMKK2 kinase domain which is conserved in Ssp1. Mutation of these residues in the binding site impaired CaMKK2 activation by αKG. Consequently, mutation of these binding sites on Ssp1 resulted in decreased Ssp2 activation. We also reveal the cellular outcomes of this novel phosphorylation of CaMKK2 and uncover new opportunities for cancer treatment strategies aimed at suppressing cell proliferation in the nutrient-poor tumour microenvironment.